Although this invention is being disclosed in connection with cervical cancer, it is applicable to many other areas of medicine. Uterine cervical cancer is the second most common cancer in women worldwide, with nearly 500,000 new cases and over 270,000 deaths annually (IARC, “Globocan 2002 database,” International agency for research in cancer, 2002, incorporated herein by reference). Because invasive disease is preceded by pre-malignant Cervical Intraepithelial Neoplasia (CIN), if detected early and treated adequately, cervical cancer can be universally prevented (D. G. Ferris, J. T. Cox, D. M. O'Connor, V. C. Wright, and J. Foerster, Modern Colposcopy. Textbook and Atlas, pp. 1-699, American Society for Colposcopy and Cervical Pathology, 2004, incorporated herein by reference). Colposcopy is the primary diagnostic method in the United States to detect CIN and cancer following an abnormal cytological screen (Papanicolaou or “pap” smear). The purpose of a colposcopic examination is to identify and rank the severity of lesions, so that biopsies representing the highest-grade abnormality can be taken, if necessary. Pre-cursor lesions of cervical cancer and invasive cancer exhibit certain distinctly abnormal morphological (relating to form and structure) features that can be identified during the colposcopic examination (A. Stafl, R. F. Mattingly, Colposcopic diagnosis of cervical neoplasia, Obstet. Gynecol 168-76 (1973), incorporated herein by reference; M. Coppelson, J. C. Dalrymple, K. H. Atkinson, Colposcopic differentiation of abnormalities arising in the transformation zone, Contemp Colposcopy, 83-110 (1993), incorporated herein by reference; R. Reid, E. P. Krums, B. R. Herschman, et al., Genital warts and cervical cancer V: The tissue basis of colposcopic change, Am. J Obstet. Gynecol, 293-303 (1984), incorporated herein by reference; J. L. Benedet, G. H. Anderson, D. A. Boyes, Colposcopic diagnosis of invasive and occult carcinoma of the cervix, Obstet. Gynecol., 557-562 (1985), incorporated herein by reference).
Among the colposcopic signs that identify pre-cancerous regions are abnormal vascular patterns called punctation and mosaic. Atypical vessels are major diagnostic features (R. Reid, E. P. Krums, B. R. Herschman, et al., Genital warts and cervical cancer V: The tissue basis of colposcopic change, Am. J. Obstet. Gynecol., 293-303 (1984), incorporated herein by reference; R. Reid and P. Scalzi, Genital warts and cervical cancer VII: An improved colposcopic index for differentiating benign papillomaviral infections from high-grade cervical intraepithelial neoplasia, Am. J Obstet. Gynecol. 153(6): 611-618. 1985, incorporated herein by reference). As such, automated methods to detect and characterize abnormal vascular patterns in digital cervical imagery are desirable to assist the physician during the diagnostic process. Accounts of semi-automatic analysis of cervical vascular patterns have been presented by Ji et al. (Q. Ji, J. Engel, and E. Craine, Classifying cervix tissue patterns with texture analysis, Pattern Recognition 33, 1561-1573 (2000), incorporated herein by reference; Q. Ji, J. Engel, and E. Craine, Texture analysis for classification of cervix lesions, IEEE Trans. Med. Imag. 19, 1144-1149 (2000), incorporated herein by reference). Results on detecting mosaic patterns using color and geometric features have been reported by Srinivasan et al. (Y. Srinivasan, D. Hernes, B. Tulpule, S. Yang, J. Guo, S. Mitra, et al., A probabilistic approach to segmentation and classification of neoplasia in uterine cervix images using color and geometric features, Proc. of SPIE 5747, 995-1003, (2005), incorporated herein by reference). A fully automated approach for the detection and characterization of punctation and mosaic has been presented by Li et al. (W. Li and A. Poirson, Detection and characterization of abnormal vascular patterns in automated cervical image analysis, Lecture Notes in Computer Science—Advances in Visual Computing 4292, 627-636 (2006), incorporated herein by reference).
Atypical blood vessels are superficial vessels that exhibit bizarre variations in diameter, course, spacing, and branching patterns, when compared with normal blood vessels. A schematic of atypical blood vessels is presented in FIG. 1. The atypical vessels are generally very dilated in comparison with other typical capillaries seen on the cervix. Atypical blood vessels traverse superficially (near to the surface or just under the skin) within the epithelium, often oriented parallel to the surface. Although normal variants may be seen, atypical vessels are most commonly associated with invasive cancer (D. G. Ferris, J. T. Cox, D. M. O'Connor, V. C. Wright, and J. Foerster, Modern Colposcopy. Textbook and Atlas, pp. 1-699, American Society for Colposcopy and Cervical Pathology, 2004, incorporated herein by reference).
Blood vessels in benign epithelia (normal tissue) branch in a tree-like fashion with wide trunks gradually giving rise to both large and small branches. However, atypical vessels may display an abrupt change in diameter or irregularly varying caliber (diameter). These vessels also exhibit random directionality, changing their direction suddenly. Moreover, atypical vessels are superficially positioned and covered by very few layers of epithelium. Compared to regular vessel patterns, the intercapillary distances are greater in atypical vessels. Early signs of cancer may be demonstrated by normal, to slightly increased, vessel spacing. In invasive cancer, most capillaries are spaced about 300 μm (micrometers or millionths of a meter) apart and, as the stage of invasive cancer increases, the percentage of atypical vessels with intercapillary distances greater than 450 μm increases proportionally. In addition, atypical vessels are distributed randomly or non-uniformly. The number of atypical blood vessels increases as the severity of cancer increases. In early stage cancers, only a few atypical vessels can typically be seen. Atypical vessels are rare in dysplasia (<0.7%), but more common in CIN3 (3% to 17%) and early invasion (44% to 77%). Atypical vessels become most common in invasive cancer (84% to 97%). Atypical blood vessels associated with cancer have been described and categorized subjectively as resembling corkscrews, tadpoles, hairpins, spaghetti, and other unusual configurations. The atypical blood vessels of adenocarcinoma, a cancer originating in the glandular tissue, have been described as resembling tendrils, roots, willow branches, and waste threads. They may arise from alterations of central loop capillaries within the columnar epithelium lining the uterus.
The present invention presents a systematic framework that automatically detects and characterizes atypical vessels in digital cervical imagery. The following patents and patent applications may be considered relevant to the field of the invention:
U.S. Patent Application Publication No. 2008/0159604 to Wang, Allan et al., incorporated herein by reference, discloses an apparatus and method for determining an extent of vascularization in which (i) a digital representation of blood vessels in a selected area is generated; (ii) one or more statistical quantitative measures for the blood vessels in the selected area are calculated; and (iii) the one or more statistical quantitative measures are compared to corresponding statistical standards to determine an extent of vascularization. The statistical quantative measures may include the density of branch points and the density of end points in a skeleton representing the blood vessels and a fractal dimension for the skeleton.
U.S. Patent Application Publication No. 2007/0287897 to Faris, Gregory, incorporated herein by reference, discloses an in vivo optical imaging system and method of identifying unusual vasculature associated with the angiogenic vasculature in tumors. An imaging system acquires images through the breast. Benign, noninvasive oxygen and carbon dioxide are used as vasoactive agents and administered by inhalation to stimulate vascular changes. Images taken before and during inhalation are subtracted. An optical vascular functional imaging system monitors abnormal vasculature through optical measurements on oxy- and deoxy-hemoglobin during inhalation of varying levels of oxygen and carbon dioxide.
U.S. Patent Application Publication No. 2007/0019846 to Bullitt, Elizabeth et al., incorporated herein by reference, discloses systems, methods, and computer program products for analysis of vessel attributes for diagnosis, disease staging, and surgical planning. A method for analyzing blood vessel attributes may include developing an atlas including statistical measures for at least one blood vessel attribute, which can be developed from blood vessel image data from different individuals. Blood vessel attribute measurements can be obtained from an individual subject and compared to the statistical measures in the atlas.
U.S. Pat. No. 7,074,188 to Nair et al., incorporated herein by reference, discloses a system and method for using backscattered data and known parameters to characterize vascular tissue. In one embodiment, an ultrasonic device is used to acquire radio frequency backscattered data—i.e. intravascular ultrasound (“IVUS”) data—from a blood vessel to create an IVUS image using a computing device. The vessel is cross-sectioned to identify its tissue type and create a corresponding (histology) image. A region of interest, preferably corresponding to the identified tissue type, is identified on the histology image, and the computing device identifies a corresponding region on the IVUS image, after which the IVUS data that corresponds to the region of interest is identified. Signal processing is performed to identify at least one parameter, which is stored in a database along with the tissue type. In another embodiment, the characterization application is adapted to receive IVUS data, determine parameters related thereto, and use the parameters stored in the database to identify a tissue type.
U.S. Pat. No. 6,351,663 to Flower et al., incorporated herein by reference, discloses methods (i) for enhancing the clarity of fluorescent dye angiograms using relatively high dye concentrations; (ii) for determining the direction of blood flow within a blood vessel using fluorescent dye angiograms; (iii) of identifying blood vessels that feed a lesion, such as a choroidal neovascularization or tumor; and (iv) of reducing the flow of blood into lesions incorporating dye-enhanced photocoagulation.
U.S. Pat. No. 6,236,886 to Cherepenin et al., incorporated herein by reference, discloses a method of obtaining tomographic images of the human body and also discloses electrical impedance tomography, in which a source of electric current is used to send electric current at levels undetectable by a human being to pairs of electrodes, between which at least two electrodes are placed. An algorithm of image reconstruction makes it possible to obtain the distribution of absolute conductivity of a body, characterizing the state of soft and bone tissues and blood vessels.
U.S. Pat. No. 6,221,623 to Smith-McCune et al., incorporated herein by reference, discloses biochemical methods for detecting cervical dysplasia. Primary screening is effected by measuring a biochemical marker of apoptosis and/or angiogenesis in each of a population of cells derived from convenient, superficial swabbing, scraping or lavage of superficial epithelial cells from the cervix, wherein the marker indicates the presence of cervical dysplasia in the sample, and scoring the results of the measuring step for cervical dysplasia—i.e., ascertaining whether or not the marker is present—in the patient in the absence of any cytological examination.
U.S. Pat. No. 6,135,965 to Tumer et al., incorporated herein by reference, discloses an apparatus and methods for spectroscopic detection of tissue abnormality, particularly precancerous cervical tissue, using neural networks to analyze in vivo measurements of fluorescence spectra.
U.S. Pat. No. 5,462,059 to Ferrara et al., incorporated herein by reference, discloses a method for assessing and displaying vasculature in a tissue mass using ultrasound and optimal velocity dependent data acquisition to differentiate between received signals from stationary tissue and received signals from slowly moving blood.